Apparatuses and methods for setting an electrical dose

ABSTRACT

Methods and apparatuses for setting a therapeutic dose of a neuromodulator implanted into a patient are described. The therapeutic dose typically includes a therapeutic dose duration including a ramp-up time to reach a peak modulation voltage and a sustained peak modulation time during which the voltage is sustained at the peak modulation voltage. The methods and apparatuses described herein may use a testing ramp to identify a peak modulation voltage that is patient-specific and provides a maximized therapeutic effect while remaining comfortably tolerable by the patient during the application of energy by the neuromodulator.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent is a continuation of U.S. patent application Ser. No.16/379,053, filed on Apr. 9, 2019, titled “APPARATUSES AND METHODS FORSETTING AN ELECTRICAL DOSE,” now U.S. Publication No.US-2019-0308020-A1, which claims priority to U.S. Provisional PatentApplication No. 62/655,122, filed on Apr. 9, 2018, titled “APPARATUSESAND METHODS FOR SETTING AN ELECTRICAL DOSE,” each of which is hereinincorporated by reference in its entirety.

This patent may be related to one or more of: U.S. patent applicationSer. No. 15/510,824, titled “NERVE CUFF ELECTRODE FOR NEUROMODULATION INLARGE HUMAN NERVE TRUNKS” and filed on Sep. 12, 2014, which claimspriority to U.S. patent application Ser. No. 14/276,200 (now U.S. Pat.No. 8,983,612) filed May 13, 2014; which is a continuation of U.S.patent application Ser. No. 13/474,926 filed May 18, 2012 now U.S. Pat.No. 8,731,676; which claims priority to U.S. patent application Ser. No.61/487,877 filed May 19, 2011, each of which is expressly incorporatedby reference herein in its entirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference in their entirety to the sameextent as if each individual publication or patent application wasspecifically and individually indicated to be incorporated by reference.

FIELD

The inventions described herein relate to the field of implantableneuromodulators.

BACKGROUND

Implantable neuromodulators (e.g., implantable neurostimulators) areincreasingly used to treat pain and other indications, in many cases bythe direct application of electrical energy to one or more nerves,including nerve bundles. Such electrical modulation may be used toexcite or inhibit nerves, or both. An implantable neuromodulator may beimplanted on, around or adjacent to a patient's nerve or nerves for thedelivery of electrical energy.

For example, electrical modulation may be applied to a nerve to treatthe unwanted and/or uncoordinated generation of nerve impulses which mayotherwise be a disabling factor in some medical conditions.Uncoordinated motor signals may produce spasticity in stroke, cerebralpalsy, multiple sclerosis, and other conditions and may lead to pain,including pain resulting from amputation. The uncoordinated signals mayresult in the inability to make desired functional movements.Involuntary motor signals in conditions including tics, choreas, and soon, may produce unwanted movements. Unwanted sensory signals can causepain.

Electrical modulation to treat a patient is generally sensitive to theamount, during and intensity of the applied energy. For example, onenon-limiting type of electrical therapy is applying high-frequencyalternating current (HFAC) to nerves that has been shown to block nerveactivity, e.g., in the treatment of pain. An appropriate dose (e.g., theamount of electrical energy applied to the patient for effectivetreatment) may be set so that it causes the desired effect, such asinhibition of nerve activity to reduce pain. On the other hand, aninappropriate dosing may lead to no effect or possibly to irritation ofthe nerve.

Unfortunately, determining proper dosing for a patient may betime-intensive, and complicated. Further, the optimal dosing to treat apatient may be highly variable between patients, and indeed, even overtime in the same patient. Thus, it would be beneficial to provide amethod and/or apparatus for simplifying and reliably setting patientdosing. Described herein are methods and apparatuses that may addressthese needs.

SUMMARY OF THE DISCLOSURE

Described herein are methods and apparatuses (devices, systems, etc.,including neuromodulators and systems including them) for setting thetherapeutic dosing of a neuromodulator that is implanted into a patient.A therapy dose typically includes a therapeutic dose duration includinga therapy ramp-up time to reach a peak modulation voltage and asustained peak modulation time during which the voltage is sustained atthe peak modulation voltage. The setting processes described herein mayadjust (e.g., set) the peak voltage of ramp to a voltage that is beyondthe patient's nerve activation level and within a nerve blocking level.The dose parameters may also include the waveform parameters applied,e.g., pulsatile or repeating (e.g., sinusoidal, square wave, saw-tooth,biphasic, etc.), and the frequency of the applied waveform (e.g., thehigh-frequency component). Other dose parameters may include the initial(e.g., starting) voltage, which may be, e.g., zero, or may be a minimumpatient-detectable modulation voltage that is determined as describedherein. In some variations, the therapeutic dose includes at last twoparts; an initial ramp-up portion in which the voltage increases fromthe initial voltage up to a peak modulation voltage, and a plateauportion, referred to as a sustained peak modulation time, during whichthe voltage is sustained at the peak modulation voltage. The duration ofthe ramp-up portion may be referred to as the ramp-up time. The durationof the second portion may be referred to as the plateau time. In somevariations, these two portions may repeat and/or alternate.

The methods and apparatuses described herein may use a testing rampapplied by the implanted neuromodulator to identify a peak modulationvoltage that is patient-specific and provides that patient with amaximal therapeutic effect while remaining comfortably tolerable by thepatient during the application of energy by the neuromodulator. Thetesting ramp may be applied as part of a therapy dose-setting procedureduring which a ramped voltage, having the same or a similar frequency asthe therapeutic dose will have, is applied by the implantedneuromodulator. Feedback, either direct (such as patient reporting) orindirect (e.g., from patient biometrics) or both may be used to selectthe target sensation intensity modulation voltage. The target sensationintensity modulation voltage identified during the testing rampapplication may be used, along with the intended therapeutic ramp-uptime to determine the therapeutic dose peak modulation voltage. Thus,the methods and apparatuses described herein may, using a single testincluding a ramp-up in voltage intensity, determine an optimal dosage.

In the absence of the teachings described herein, it is difficult todetermine an optimal dosage at which the applied voltage is increase toa peak and sustained for sufficiently long to achieve a therapeuticbenefit. The inventors have found that although it is generallybeneficial to apply as high a voltage as possible to the patient,particularly (but not exclusively) in applications in which neuralmodulation comprises high-frequency (e.g., greater than 1 kHz)modulation from an implanted neuromodulator to inhibit activity of anerve or nerve bundle, there is a difficulty to define voltagethreshold, above which further voltage amplitude may result in painand/or discomfort for the patient. This threshold is not only variablebetween different patients, but may vary with respect to the individualpatient. For example, patient sensitivity appears to depend at leastslightly on the rate of increase of the voltage. Slower ramp-up timesmay generally permit a higher final voltage. However, inventors havealso found that it is beneficial to maintain the therapeutic modulationsuch that a longer time is spent at the maximum voltages (e.g., thesustained or plateau period). Surprisingly, the inventors have foundthat it is possible to use a target sensation intensity modulationvoltage that is specific to the patient from the test voltage ramp andscale this target sensation intensity modulation voltage for otherramps, which may allow for the use of a single setting (e.g., therapydose-setting) procedure to determine the target sensation intensitymodulation voltage from a known ramp-up to be used to determine atherapeutic peak modulation voltage, as described in detail herein.

Note that the target sensation intensity modulation voltage may be thevoltage that induces a target intensity of sensation in the patientduring the test. More specifically, this target sensation intensitymodulation voltage may be the maximum voltage that the patient cantolerate for the therapy period.

In any of the methods described herein, the testing may be performed ona patient after a period of inactivity (non-modulation) of theneuromodulator device. For example, there may be a recovery periodduring which the maximum voltage to induce the target intensity ofsensation may change, and be unreliable. Thus, the method may have adelay period before applying the test ramp. This delay may be 1 minuteor more, 5 minutes or more, 10 minutes or more, 15 minutes or more, 20minutes or more, 25 minutes or more, 30 minutes or more, 35 minutes ormore, 40 minutes or more, 1 hour or more, etc. The testing period mayitself be brief (e.g., one or more trials of 30 min or less, which maybe separated by this delay period).

In general these methods may be applied to, but are not limited to, theuse with neuromodulation to provide a high-frequency block of a nerve orbundle of nerves. For example, these methods and apparatuses may be usedto set and/or optimize therapy treatment dosing for a high-frequencyblock of a nerve such as the sciatic nerve, dorsal root ganglion (DRG),etc.

For example, described herein are methods of setting a therapeutic doseof a neuromodulator implanted into a patient, wherein the therapeuticdose comprises a therapeutic dose duration including a therapy ramp-uptime to reach a peak modulation voltage and a sustained peak modulationtime during which the voltage is sustained at the peak modulationvoltage. The method may include: applying a test voltage ramp from theneuromodulator implanted into the patient; determining a targetsensation intensity modulation voltage that is specific to the patientfrom the test voltage ramp; estimating the peak modulation voltage as afunction of the target sensation intensity modulation voltage and thetherapy ramp-up time to reach the peak modulation voltage; and settingthe therapeutic dose using the estimated peak modulation voltage.

The target sensation intensity modulation voltage may be a maximumpatient-tolerable modulation voltage.

In general, the therapy ramp-up time may be any appropriate portion ofthe therapeutic dose duration, such as between about 10% and about 90%(e.g., between about 30% and about 70%, between about 40% and about 60%,between about 45% and about 55%, about 50%, etc.). For example, thetherapy ramp-up time to the peak modulation voltage may be set to behalf of the therapeutic dose duration. The balance of the therapeuticdose duration may be the plateau period (e.g., the sustained peakmodulation time). As mentioned, above, in some variations, thetherapeutic dose may then repeat, either immediately or more preferablyafter a “lockout” period during which modulation is not applied by theneuromodulator. The lockout period may be 5 minutes or more (e.g., 5minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes,etc.).

The therapeutic dose duration may be any appropriate length of time,e.g., between about 5 minutes and about 2 hours, e.g., between about 10minutes and 1 hours, between about 15 minutes and 50 minutes, betweenabout 20 minutes and 45 minutes, between about 25 minutes and about 40minutes, etc., such as about 30 minutes.

Determining the target sensation intensity modulation voltage mayinclude determining the voltage of the test voltage ramp being appliedwhen a patient-reported feedback indicating the strongest sensation thatthe patient can tolerate for a therapeutic dose is received during theapplication of the test voltage ramp. During the application of thevoltage ramp, for example, the patient may self-report on theexperienced sensation from the applied voltage ramp. In particular, thepatient may report (verbally, by activating a control such as a button,touchscreen, etc.) that the sensation is first felt and/or barelynoticeable, and/or when the sensation is strong (e.g., “strong but doesnot bother me”) and/or very strong (e.g., the “strongest sensation I cantolerate for the treatment period”).

In general, estimating the peak modulation voltage as a function of thetarget sensation intensity modulation voltage and therapy ramp-up timemay include estimating the peak modulation voltage as a product of afunction of the therapy ramp-up time and a function of the targetsensation intensity modulation voltage. For example, estimating the peakmodulation voltage as a function of the target sensation intensitymodulation voltage and therapy ramp-up time may comprise estimating thepeak modulation voltage as a square root of a product of the therapyramp-up time and the target sensation intensity modulation voltage.

Any of these methods may also include determining a minimumpatient-detectable modulation voltage that is specific to the patientfrom the test voltage ramp and further wherein setting the therapeuticdose comprises using the minimum patient-detectable modulation voltageas a starting voltage for the therapeutic dose. For example, determiningthe minimum patient-detectable modulation voltage may include receivingpatient reported feedback during the application of the test voltageramp, as mentioned above.

In general, setting the therapeutic dose may include setting thetherapeutic dose in the implanted neuromodulator or a controller incommunication with the implanted neuromodulator. Setting the therapeuticdose may also include setting one or more of: the therapeutic doseduration, the therapy ramp-up time to reach the peak modulation voltage,and the sustained peak modulation time. These parameters may be set forthe test voltage ramp.

In general, the applied therapeutic energy may include a high-frequencymodulation signal (waveform) that is ramped up to a plateau value. Asmentioned above, any of these methods may also include setting thefrequency of the high-frequency component of the test voltage rampapplied and setting a frequency of the high-frequency component of thetherapeutic dose to the frequency of the high-frequency component of thetest voltage ramp applied. For example, the frequency of thehigh-frequency component of the test voltage ramp applied may be between1 kHz and 100 kHz.

Any of these methods may also include setting an alternative therapeuticdose of the neuromodulator implanted into a patient. The alternativetherapeutic dose may comprise an alternative peak modulation voltagethat is between about 60% and 95% of the peak modulation voltage. Thealternative therapy dose may be provided to allow the patient to applyone or the other therapy doses (the therapy dose or the alternativetherapy dose) at their preference.

For example, a method of setting a therapeutic dose of a neuromodulatorimplanted into a patient, wherein the therapeutic dose comprises atherapeutic dose duration including a therapy ramp-up time to reach apeak modulation voltage and a sustained peak modulation time duringwhich the voltage is sustained at the peak modulation voltage, mayinclude: applying a test voltage ramp from the neuromodulator implantedinto the patient; determining a minimum patient-detectable modulationvoltage that is specific to the patient from the test voltage ramp;determining a target sensation intensity modulation voltage that isspecific to the patient from the test voltage ramp; estimating the peakmodulation voltage as a product of a function of the target sensationintensity modulation voltage and a function of the therapy ramp-up timeto reach the peak modulation voltage; and setting the therapeutic doseusing the estimated peak modulation voltage and using the minimumpatient-detectable modulation voltage as a starting voltage for thetherapeutic dose.

Also described herein are systems that are configured to implement anyof the methods described herein either automatically orsemi-automatically. For example, a system may include: an implantableneuromodulator; a controller for controlling the application of atherapeutic dose by the neuromodulator, wherein the therapeutic dosecomprises a therapeutic dose duration including a therapy ramp-up timeto reach a peak modulation voltage and a sustained peak modulation timeduring which the voltage is sustained at the peak modulation voltage,the controller comprising one or more processors; memory coupled to theone or more processors, the memory configured to store computer-programinstructions, that, when executed by the one or more processors,implement a computer-implemented method, the computer-implemented methodcomprising: applying a test voltage ramp from the neuromodulatorimplanted into the patient; determining a target sensation intensitymodulation voltage that is specific to the patient from the test voltageramp; estimating the peak modulation voltage as a function of the targetsensation intensity modulation voltage and the therapy ramp-up time toreach the peak modulation voltage; and setting the therapeutic doseusing the estimated peak modulation voltage.

The computer-implemented method may include any of the steps describedabove, which may be implemented by the controller. For example, whendetermining a target sensation intensity modulation voltage that isspecific to the patient from the test voltage ramp, the controller mayprompt the patient or otherwise allow the patient to enter theirreported sensation induced by the ongoing modulation.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe claims that follow. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 shows one example of a neuromodulation system (showing a nervecuff, lead and implantable controller/waveform generator).

FIG. 2 shows an example of the system of FIG. 1 implanted into a patient(also showing a controller (in this example, an external controller) forcontrolling and applying a therapeutic dose.

FIG. 3A is an example of a schematic of a voltage profile of atherapeutic dose.

FIG. 3B illustrates examples a schematic of the voltage profiles of twotherapeutic doses that may be applied by an implanted neuromodulator asdescribed herein.

FIG. 3C illustrates another example of a voltage profile of atherapeutic dose.

FIG. 4 is a flow diagram illustrating one method of setting atherapeutic dose for an implantable neuromodulator as described herein.

FIGS. 5A-5H are tables that may be used to determine a therapeutic dose.FIGS. 5A-5H include test parameter setting (FIGS. 5A and 5B), timeelapsed and therapy induced sensation described by subject (FIG. 5C),initial amplitude based on time when induced sensation was “first felt”(FIG. 5D), look-up tables to determine final amplitude (Vp) based on thestrength of the induced sensation (FIG. 5E) and a discounted finalamplitude for a second, alternative, dose (FIG. 5F). FIGS. 5G and 5H aretables illustrating test parameters, including the final parametersettings determined from FIGS. 5A-5G.

FIGS. 6A-6C are tables that may be used in one method for adjustingtherapeutic dose.

DETAILED DESCRIPTION

In general, the methods and apparatuses for performing them describedherein allow optimized dose setting of a neuromodulation apparatus sothat the therapy dose provided by the neuromodulator maximizes theenergy which may enhance the effect of the neuromodulation on the targetnerve(s) without irritating or harming the patient. These methods andapparatuses may be generally described for use with an implantedneuromodulator, but may be also or alternatively be used with externalneuromodulators or neuromodulators prior to implantation. Further, theexamples provided herein are provided in reference to neuromodulatoryinhibition by the application of high-frequency neuromodulation, howeverthese methods and apparatuses may also be used with otherneurostimulatory regimes including general neuromodulation. Examples ofneuromodulator apparatuses and methods that may benefit from thesemethods and apparatuses may include, for example, spinal cordstimulators (SCS) and any other neuromodulation application that may beimproved by the optimization between therapeutic benefit and inducedsensation.

The inventors have generally found that increasing the applied voltageof neuromodulation is beneficial, particularly when sustained at a highvoltage (e.g., high peak voltage). However, high voltage neuromodulationapplied to a patient's nerve may result in pain and discomfort when themodulation exceeds a threshold voltage during the ramp up to thesustained high voltage. The value of this threshold may vary betweenpatients and also appears to vary based on the recent modulation alreadyexperienced by the nerve as well as the modulation parameters (e.g.,frequency). In general, a slower ramp up to a peak modulation voltage ina therapeutic dose may result in lower intensities of induced sensation,and therefore correspondingly higher peak modulation voltages. However,it is also beneficial for a therapeutic dose to maintain the peakmodulation voltage for as long as possible during the therapeutic dose.

Described herein are methods of determining a target sensation intensitymodulation voltage using a generic test ramp and adapting this targetintensity of modulation to determine an optimal peak modulation voltagefor neuromodulation.

These methods and apparatuses may be used with any appropriateneuromodulator. FIG. 1 illustrates one example of an implantableneuromodulator including a nerve cuff 101, a lead 103 connecting thenerve cuff to a controller (e.g., waveform generator, control circuitry,power source, communications circuitry and/or antenna, etc.) 105.Systems including a nerve cuff such as those described herein, may beused, for example, to apply a high frequency nerve block to acutelytreat pain, either acute pain or chronic pain (more than 6 months induration), in humans by blocking nerve conduction on an actionpotential. Acute treatment may refer to on-demand treatment withsubstantially immediate pain relief effect. The nerve cuff may beapplied onto a moderate and relatively large diameter nerves such as thesciatic nerve. One therapy involves reversibly blocking peripheralnerves by applying high frequency alternating current directly on anerve trunk. Specifically, a current ranging from 1 kHz to 100 kHz(e.g., 5 kHz to 50 kHz) may be applied; this may be referred to as ahigh frequency modulation, compared to a current of less than 1 kHzapplied in the conventional electrical modulation described above.Efficacy of the high frequency alternating current therapy in acutenon-human animal experiments (frog, cat) has been reported. U.S. Pat.Nos. 7,389,145 and 8,060,208 describe in general this electricalmodulation technology.

The nerve cuffs may encircle a particular segment of a targetedperipheral nerve, e.g., a sciatic nerve, a tibial nerve, etc. Using animplanted electrode connected to an electrical waveform generator, anelectrical waveform may be applied for a time interval, e.g., 10 min (15min, 20 min, 25 min, 30 min, 35 min, 40 min, etc.), sufficient to effectsubstantially immediate patient pain relief, e.g., within 10 min, and anextended period of pain relief up to several hours. The current mayrange, for example, from 4 mApp to 26 mApp.

The application of 10 kHz alternating current generated by a customgenerator via a custom implanted nerve electrode may significantlyreduce pain in the majority of patients treated. For example, animplantable electrode operatively connected to an external or implantedwaveform generator may be used. The electrode may be a spiral cuffelectrode similar to that described in U.S. Pat. No. 4,602,624. Theelectrode may be implanted in a human mammal on a desired peripheralnerve trunk proximal to the pain source (e.g., a neuroma), such that thecuff encircled the desired peripheral nerve in which the actionpotential was to be blocked. The cuff inner diameter may range fromabout 4 mm to about 13 mm. The sciatic nerve is known to have arelatively large nerve trunk; the diameter of the proximal part of thesciatic nerve in a human adult is about 12 mm. In one embodiment, theapparatus and method was used on the sciatic nerve to treat limb pain inabove knee amputees. In one embodiment, the apparatus and method wasused on the tibial nerve to treat limb pain in below knee amputees.

For example, FIG. 2 illustrates the use of a system including a cuffelectrode applied to the sciatic nerve of an amputee patient. In thisexample, the amputee 107 has been implanted with a nerve cuff 101 aroundthe sciatic nerve (nerve trunk), and is connected, via a lead 103, tothe controller including the waveform generator 105. This procedure maybe done, for example, by first dissecting to expose the nerve in an openprocedure, then wrapping the nerve with the flexible (self-closing)cuff. Once implanted the controller/waveform generator may be placed ina pocket in the anterorlateral abdominal wall, and a tunneling electrodecable may be positioned along the midaxilalary line (includingtransversely across the abdomen) to connect the controller/waveformgenerator to the nerve cuff electrode. Once the impedance of the nervecuff is checked (e.g., by the controller) the incisions may be closed.The incision for implanting the nerve cuff is typically larger thanabout 1.5 inches (e.g., between 1.5 and 3 inches), so that sufficientvisualization and access may be achieved. Once implanted and allowed toheal, the implanted neuromodulator may be set as described herein toprovide an optimized therapeutic dose as described herein.

The system shown in FIG. 2 also includes a controller 131, shown as anexternal controller that include one or more processors and may beconfigured to perform the methods described herein. The controller, or aseparate device coupled to the controller, may include an input for theuser to report the sensation induced by the applied modulation,including the test ramp, as will be described in greater detail below.

In general a therapeutic dose for a neuromodulator may have at least twoportions. FIG. 3A illustrates one example of an exemplary voltageprofile of a therapeutic dose. In this example, the first portion of thetherapeutic dose is a ramp-up period 303, which has a duration (referredto as a therapy ramp-up time to reach a peak modulation voltage, V₁ inFIG. 3A) of T_(plateau) that is between 10% and 90% of the totalduration of the therapeutic dose (T_(duration)). The second portion ofthe therapeutic dose is a sustained peak modulation time 305 duringwhich the voltage is sustained at the peak modulation voltage (V₁), thismay also be referred to as the plateau portion.

During the ramp-up portion of the therapeutic dose, the neuromodulatormay apply an increasing intensity of modulation from the start (time 0,T₀) to the peak modulation voltage (V₁) at time T_(plateau). In FIG. 3Athis ramp period is shown as a linear increase, however it may increasein steps (e.g., incrementally increase following regular interval, suchas increasing by 0.5 V every 30 seconds, etc.). In practice, themodulation may be applied with a high-frequency component having afrequency of between about 1 kHz and 100 kHz (e.g., 1 kHz and 50 kHz, 1kHz and 40 kHz, 1 kHz and 30 kHz, 1 kHz and 25 kHz, about 5 kHz, about10 kHz, etc.).

FIG. 3B illustrates another example of a pair of therapeutic doseprofiles. In one example 309, a rapid ramp up reaches a first voltagelevel (V₂), and is held at this first voltage level for the duration ofthe dose. This first voltage level may result in a first sensationintensity for the patient, including a sensation intensity that is themaximum sensation that can be tolerated for the dose. The second profile311 shows an example in which an approximately equivalent sensationintensity for the patient may be experienced, but with a much highvoltage (V₃) that is reached by ramping up over a longer time period(shown as T_(1/2), approximately half of the duration of the dose,T_(duration)). In this example, although the time at which themodulation applied is at the maximum peak voltage is longer for thefirst profile, the second profile has a much higher maximum peakvoltage. In practice, once a maximum peak voltage is determined, a doseprofile may be set for the neuromodulator by using a starting voltage(which may be determined from the minimum patient-detectable modulationvoltage detectable by the patient) the peak modulation voltage (whichmay be determined as described herein) the ramp-up time to reach thepeak modulation voltage, and either or both the total duration of thedose and/or the plateau duration, or equivalent values from which thesevalues may be derived. The ramp-up time to reach the peak modulationvoltage may be expressed as a time, or as a rate of voltage increase.The therapeutic dose may also include the waveform parameters to beapplied (e.g., pulsed, such as sinusoidal), and the high-frequencycomponent (e.g., between 1 kHz and 100 kHz, between 1 kHz and 50 kHz,e.g., about 5 kHz, about 10 kHz, etc.), etc.

In general, the maximum peak voltage may be determined empirically forany patient by applying a test ramp. The test ramp is a test voltageramp from the neuromodulator implanted into the patient. While applyingthe test ramp, the patient may be interrogated (either manually orautomatically) to determine the intensity experienced by the patientfrom the modulation. In particular, the patient may be interrogated todetermine the first point at which the modulation becomes eithernoticeable or consistently perceived (e.g., a minimum patient-detectablemodulation voltage). In some variations, this value may be used as thestarting voltage during the therapeutic dose. The patient may also beinterrogated to determine the target sensation intensity modulationvoltage to be applied during the therapy dose. In some variations, thismay be the maximum patient-tolerable modulation voltage.

The patient may be interrogated by prompting and/or receiving patientself-reported sensations. These sensations may be ranked (e.g., 1,corresponding to “I just started to feel the therapy;” 2, correspondingto “I only notice it when I pay attention to it;” 3, corresponding to“strong sensation but it doesn't bother me;” 4, corresponding to“strongest sensation that I can tolerate for 15-20 min;” and 5,corresponding to “I cannot tolerate this sensation for longer than a fewminutes”). The apparatus may include an input that receives the patientintensity reporting and correlates intensity input to the appliedvoltage and/or the time during which the intensity was reported (whichis equivalent information).

Alternatively, in some variations the apparatus may interrogate thepatient indirectly, by monitoring patient biometric information (heartrate, pulse, blood pressure, ensemble nerve activity, skin conductance,respiration, biomarker, including pain biomarker, levels, etc.) that mayalso be correlated with this applied ramp to determine a targetsensation intensity modulation voltage, including a maximumpatient-tolerable modulation voltage.

Based on the identified voltage of the target sensation intensity fromthe applied test ramp, the method and/or apparatus may determine atarget sensation intensity modulation voltage that is specific to thepatient. This target sensation intensity modulation voltage (e.g.,V_(s)) may then be used to calculate, e.g., estimate, the peakmodulation voltage (V_(p)) in conjunction with the intendent therapyramp-up time to reach this peak modulation voltage (T_(p)). Although theintended ramp-up time may be set to different values (typically between10% and 90% of the total duration of the therapeutic dose), it may beset to, for example, half of the duration of the therapeutic dose (e.g.,T_(1/2)). For example, the peak voltage may be set to be:

V _(p)=√(T _(p) ×V _(s))=√(T _(p) ×T _(s) ×R _(s))  (1)

As mentioned, V_(s) is the voltage of the target sensation intensitydetermined by from the test ramp, T_(p) is the ramp up time to get tothe peak voltage, and R_(s) is the ramp rate used during the test (sinceT_(s)×R_(s) is equivalent to V_(s)).

In some cases, where it is assumed that the duration of a therapeuticdose will be approximately 30 minutes, a 15 minute ramp-up time willresult in an approximation for the Vp from the identified Vs of:

Vp=4*√V _(s)  (2)

An example of this method is provided below, and shown in correspondingFIGS. 5A-6E.

Example

In one example, a maximum tolerable therapy voltage for each nerve wasdetermined using the method described above. The implanted apparatus wassimilar to that shown in FIGS. 1 and 2. Patients for which animplantable neuromodulator was implanted were allowed to heal, and thentrained to report sensations induced by modulation as:

First felt—“I just started to feel the therapy”

Weak—“I only notice it when I pay attention to it”

Strong—“Strong sensation but it doesn't bother me”

Very Strong—“Strongest sensation that I can tolerate for 15-20 min”

Too Strong—“I cannot tolerate this sensation for longer than a fewminutes

General set (e.g., pre-set) parameters for test as shown in FIG. 5A.FIG. 5B is a table illustrating the test parameter settings for theimplanted apparatus. In this device, the two doses (dose 1 and dose 1),and two channels (channel A and channel B) are available. In FIG. 5B,only one (dose 1, channel A) is used (“enabled”). As shown in FIG. 5A,the general parameters include a sinusoidal waveform shape having afrequency of 10 kHz, and an initial amplitude (Vp) or 0 V. The initialramp duration is intended to be 15 minutes plateau duration is 15 min(so the total dose duration is 30 min).

The test is started by simultaneously starting a clock and startingdose 1. The time is recorded along with the patient-reported inducedsensation strength on NRS (e.g., in this example, in table 1.2a shown inFIG. 5C) for each sensation level. In this example, this sensation maymost likely be a tingle or numbness on the medial side or foot of thephantom limb for these patients. If no sensation is felt in <5 min,abort test by clicking on “Stop Therapy” button and repeat with adifferent frequency (e.g., 5 kHz) after a rest period (e.g., 15 min ofrest) to allow nerve recovery. Pilot study data indicated that similartherapeutic effects can be achieved at lower amplitudes by using a 5 kHzsignal. When subject reports induced sensation as “Too strong”, thetherapy may be turned OFF by clicking on “Stop Therapy” button. The timemay be recorded (e.g., in Table 1.2a) as well as the subject reportedNRS rating of induced sensation

Based on the time and therefore the voltage at which the sensation wasfirst felt, a minimum patient-detectable modulation voltage that isspecific to the patient from the test voltage ramp may be determined.Table 1.3 (FIG. 5D) provide a simplified look-up table to convert thereported time into the minimum patient-detectable modulation voltage.For example, by identifying an initial amplitude corresponding to thisvalue on Table 1.3, corresponding to “First felt” time (e.g., for afirst felt time of 01:18, the value is 1.0 V).

Similarly, the target sensation intensity modulation voltage that isspecific to the patient may be determined from the test voltage rampdata. FIGS. 5E and 5F provide look-up tables that may be used toestimate the peak modulation voltage as a function of the targetsensation intensity modulation voltage and the therapy ramp-up time toreach the peak modulation voltage, where the therapy ramp-up time isassumed to be 15 minutes (e.g., half of a 30 minute dose). In thisexample, the final amplitudes for dose may be identified from table 1.4a(FIG. 5E). Alternatively equation (1), above, may be used. In thisexample, the reported intensity corresponding to “Too Strong” time(e.g., for a “Too Strong” time of 07:35, the indicated value is 11.0 V)may be used to indicate the target sensation intensity modulationvoltage.

FIG. 5F and table 1.4b provide a second, scaled peak amplitude that is0.8× the value determined from Equation 1 and table 1.4a. This seconddose may be provided as an alternative dose.

FIGS. 5G and 5H (table 1.1b) illustrate the final parameter settings forthe therapeutic dose determined as described above. In this example, thegeneral parameters may be as indicated in FIG. 5G, and the finalparameter setts may be entered into the table 1.1b shown in FIG. 5H. Forexample, the initial amplitude may be entered into the table based onthe minimum patient-detectable modulation voltage determined above. Thefinal amplitude identified (e.g., using Table 1.4a and Table 1.4b inFIGS. 5E and 5F) may be included in the final parameters. In thisexample, the lockout period is set to 0.5 hours and the frequency is setto about, e.g., 5 kHz, if testing was done at 5 kHz.

When two dose variations are given, as shown, the subject may beinstructed to use both dose 1 and dose 2 initially for several days andthen pick the one they feel is more effective in pain reduction.

In some variations, the programming (the dose information) may be set,for example every week for 3-4 weeks following the initial setting andperiodically thereafter. This may allow the method and/or apparatus toadjust the final amplitude to maximize therapy voltage within tolerablelimits of induced sensation. The method described above may be adjustedbased on patient-reported sensation. For example, the final voltage maybe adjusted as indicated in FIG. 6A (Table 2.1) and the procedureoutlined above may be repeated (e.g., to complete the tables shown inFIGS. 6B and 6C).

Any of the methods (including user interfaces) described herein may beimplemented as software, hardware or firmware, and may be described as anon-transitory computer-readable storage medium storing a set ofinstructions capable of being executed by a processor (e.g., computer,tablet, smartphone, etc.), that when executed by the processor causesthe processor to control perform any of the steps, including but notlimited to: displaying, communicating with the user, analyzing,modifying parameters (including timing, frequency, intensity, etc.),determining, alerting, or the like.

When a feature or element is herein referred to as being “on” anotherfeature or element, it can be directly on the other feature or elementor intervening features and/or elements may also be present. Incontrast, when a feature or element is referred to as being “directlyon” another feature or element, there are no intervening features orelements present. It will also be understood that, when a feature orelement is referred to as being “connected”, “attached” or “coupled” toanother feature or element, it can be directly connected, attached orcoupled to the other feature or element or intervening features orelements may be present. In contrast, when a feature or element isreferred to as being “directly connected”, “directly attached” or“directly coupled” to another feature or element, there are nointervening features or elements present. Although described or shownwith respect to one embodiment, the features and elements so describedor shown can apply to other embodiments. It will also be appreciated bythose of skill in the art that references to a structure or feature thatis disposed “adjacent” another feature may have portions that overlap orunderlie the adjacent feature.

Terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention.For example, as used herein, the singular forms “a”, “an” and “the” areintended to include the plural forms as well, unless the context clearlyindicates otherwise. It will be further understood that the terms“comprises” and/or “comprising,” when used in this specification,specify the presence of stated features, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, steps, operations, elements, components, and/orgroups thereof. As used herein, the term “and/or” includes any and allcombinations of one or more of the associated listed items and may beabbreviated as “/”.

Spatially relative terms, such as “under”, “below”, “lower”, “over”,“upper” and the like, may be used herein for ease of description todescribe one element or feature's relationship to another element(s) orfeature(s) as illustrated in the figures. It will be understood that thespatially relative terms are intended to encompass differentorientations of the device in use or operation in addition to theorientation depicted in the figures. For example, if a device in thefigures is inverted, elements described as “under” or “beneath” otherelements or features would then be oriented “over” the other elements orfeatures. Thus, the exemplary term “under” can encompass both anorientation of over and under. The device may be otherwise oriented(rotated 90 degrees or at other orientations) and the spatially relativedescriptors used herein interpreted accordingly. Similarly, the terms“upwardly”, “downwardly”, “vertical”, “horizontal” and the like are usedherein for the purpose of explanation only unless specifically indicatedotherwise.

Although the terms “first” and “second” may be used herein to describevarious features/elements (including steps), these features/elementsshould not be limited by these terms, unless the context indicatesotherwise. These terms may be used to distinguish one feature/elementfrom another feature/element. Thus, a first feature/element discussedbelow could be termed a second feature/element, and similarly, a secondfeature/element discussed below could be termed a first feature/elementwithout departing from the teachings of the present invention.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising” means various components can be co-jointlyemployed in the methods and articles (e.g., compositions and apparatusesincluding device and methods). For example, the term “comprising” willbe understood to imply the inclusion of any stated elements or steps butnot the exclusion of any other elements or steps.

In general, any of the apparatuses and methods described herein shouldbe understood to be inclusive, but all or a sub-set of the componentsand/or steps may alternatively be exclusive, and may be expressed as“consisting of” or alternatively “consisting essentially of” the variouscomponents, steps, sub-components or sub-steps.

As used herein in the specification and claims, including as used in theexamples and unless otherwise expressly specified, all numbers may beread as if prefaced by the word “about” or “approximately,” even if theterm does not expressly appear. The phrase “about” or “approximately”may be used when describing magnitude and/or position to indicate thatthe value and/or position described is within a reasonable expectedrange of values and/or positions. For example, a numeric value may havea value that is +/−0.1% of the stated value (or range of values), +/−1%of the stated value (or range of values), +/−2% of the stated value (orrange of values), +/−5% of the stated value (or range of values), +/−10%of the stated value (or range of values), etc. Any numerical valuesgiven herein should also be understood to include about or approximatelythat value, unless the context indicates otherwise. For example, if thevalue “10” is disclosed, then “about 10” is also disclosed. Anynumerical range recited herein is intended to include all sub-rangessubsumed therein. It is also understood that when a value is disclosedthat “less than or equal to” the value, “greater than or equal to thevalue” and possible ranges between values are also disclosed, asappropriately understood by the skilled artisan. For example, if thevalue “X” is disclosed the “less than or equal to X” as well as “greaterthan or equal to X” (e.g., where X is a numerical value) is alsodisclosed. It is also understood that the throughout the application,data is provided in a number of different formats, and that this data,represents endpoints and starting points, and ranges for any combinationof the data points. For example, if a particular data point “10” and aparticular data point “15” are disclosed, it is understood that greaterthan, greater than or equal to, less than, less than or equal to, andequal to 10 and 15 are considered disclosed as well as between 10 and15. It is also understood that each unit between two particular unitsare also disclosed. For example, if 10 and 15 are disclosed, then 11,12, 13, and 14 are also disclosed.

Although various illustrative embodiments are described above, any of anumber of changes may be made to various embodiments without departingfrom the scope of the invention as described by the claims. For example,the order in which various described method steps are performed mayoften be changed in alternative embodiments, and in other alternativeembodiments one or more method steps may be skipped altogether. Optionalfeatures of various device and system embodiments may be included insome embodiments and not in others. Therefore, the foregoing descriptionis provided primarily for exemplary purposes and should not beinterpreted to limit the scope of the invention as it is set forth inthe claims.

The examples and illustrations included herein show, by way ofillustration and not of limitation, specific embodiments in which thesubject matter may be practiced. As mentioned, other embodiments may beutilized and derived there from, such that structural and logicalsubstitutions and changes may be made without departing from the scopeof this disclosure. Such embodiments of the inventive subject matter maybe referred to herein individually or collectively by the term“invention” merely for convenience and without intending to voluntarilylimit the scope of this application to any single invention or inventiveconcept, if more than one is, in fact, disclosed. Thus, althoughspecific embodiments have been illustrated and described herein, anyarrangement calculated to achieve the same purpose may be substitutedfor the specific embodiments shown. This disclosure is intended to coverany and all adaptations or variations of various embodiments.Combinations of the above embodiments, and other embodiments notspecifically described herein, will be apparent to those of skill in theart upon reviewing the above description.

What is claimed is:
 1. A method of setting therapeutic doses of aneuromodulator implanted into a patient, wherein each of the therapeuticdoses comprises a therapeutic dose duration including a therapy ramp-uptime to reach a peak modulation voltage and a sustained peak modulationtime during which voltage is sustained at the peak modulation voltage,the method comprising: applying a test voltage ramp from theneuromodulator implanted into the patient; determining a targetsensation intensity modulation voltage that is specific to the patientfrom the test voltage ramp; calculating an estimated peak modulationvoltage as a function of the target sensation intensity modulationvoltage and the therapy ramp-up time to reach the peak modulationvoltage; setting a first therapeutic dose using the estimated peakmodulation voltage; and setting a second therapeutic dose using apercentage of the estimated peak modulation voltage.
 2. The method ofclaim 1, wherein the therapeutic dose duration of the first therapeuticdose is the same as the therapeutic dose duration of the secondtherapeutic dose.
 3. The method of claim 1, wherein a duration ofapplying the estimated peak modulation voltage of the first therapeuticdose is greater than a duration of applying the estimated peakmodulation voltage of the second therapeutic dose.
 4. The method ofclaim 1, wherein the therapeutic dose duration of the first therapeuticdose is the same as the therapeutic dose duration of the secondtherapeutic dose, and wherein a duration of applying the estimated peakmodulation voltage of the first therapeutic dose is greater than aduration of applying the estimated peak modulation voltage of the secondtherapeutic dose.
 5. The method of claim 1, further comprisingdetermining the therapy ramp-up time as a percentage of the therapeuticdose duration.
 6. The method of claim 1, further comprising determininga minimum patient-detectable modulation voltage that is specific to thepatient from the test voltage ramp, and further wherein the minimumpatient-detectable modulation voltage is used as a starting voltage forthe test voltage ramp.
 7. The method of claim 6, wherein determining theminimum patient-detectable modulation voltage comprises receivingpatient reported feedback during the application of the test voltageramp.
 8. The method of claim 1, wherein the target sensation intensitymodulation voltage is a maximum patient-tolerable modulation voltage. 9.The method of claim 1, wherein the therapy ramp-up time to the peakmodulation voltage is half of the therapeutic dose duration.
 10. Themethod of claim 1, wherein the therapeutic dose duration is set to be 30minutes.
 11. The method of claim 1, further comprising setting ahigh-frequency component of the test voltage ramp applied and setting ahigh-frequency component of the first therapeutic dose to thehigh-frequency component of the test voltage ramp applied.
 12. Themethod of claim 11, wherein the high-frequency component of the testvoltage ramp applied is between 1 kHz and 100 kHz.
 13. A method ofsetting therapeutic doses of a neuromodulator implanted into a patient,wherein each of the therapeutic doses comprises a therapeutic doseduration including a therapy ramp-up time to reach a peak modulationvoltage and a sustained peak modulation time during which voltage issustained at the peak modulation voltage, the method comprising:applying a test voltage ramp from the neuromodulator implanted into thepatient; determining a target sensation intensity modulation voltagethat is specific to the patient from the test voltage ramp; calculatinga first estimated peak modulation voltage as a function of the targetsensation intensity modulation voltage and the therapy ramp-up time toreach the peak modulation voltage; setting a first therapeutic doseusing the first estimated peak modulation voltage; and setting a secondtherapeutic dose using a second estimated peak modulation voltage thatis less than the first estimated peak modulation voltage, wherein aduration of applying the first estimated peak modulation voltage isgreater than a duration of applying the second estimated peak modulationvoltage.
 14. The method of claim 13, wherein the therapeutic doseduration of the first therapeutic dose is the same as the therapeuticdose duration of the second therapeutic dose.
 15. The method of claim13, further comprising determining the therapy ramp-up time as apercentage of the therapeutic dose duration.
 16. A system comprising: animplantable neuromodulator; a controller for controlling the applicationof a therapeutic dose by the neuromodulator, wherein each of thetherapeutic doses comprises a therapeutic dose duration including atherapy ramp-up time to reach a peak modulation voltage and a sustainedpeak modulation time during which voltage is sustained at the peakmodulation voltage, the controller comprising one or more processors;memory coupled to the one or more processors, the memory configured tostore computer-program instructions, that, when executed by the one ormore processors, implement a computer-implemented method, thecomputer-implemented method comprising: applying a test voltage rampfrom the neuromodulator implanted into a patient; determining a targetsensation intensity modulation voltage that is specific to the patientfrom the test voltage ramp; calculating an estimated peak modulationvoltage as a function of the target sensation intensity modulationvoltage and the therapy ramp-up time to reach the peak modulationvoltage; setting a first therapeutic dose using the estimated peakmodulation voltage; and setting a second therapeutic dose using apercentage of the estimated peak modulation voltage.
 17. The system ofclaim 16, wherein a duration of applying the estimated peak modulationvoltage of the first therapeutic dose is greater than a duration ofapplying the estimated peak modulation voltage of the second therapeuticdose.
 18. The system of claim 16, wherein the therapy ramp-up time tothe peak modulation voltage is half of the therapeutic dose duration.19. The system of claim 16, wherein the therapeutic dose duration is setto be 30 minutes.
 20. The system of claim 16, further comprisingdetermining a minimum patient-detectable modulation voltage that isspecific to the patient from the test voltage ramp, and further whereinthe minimum patient-detectable modulation voltage is used as a startingvoltage for the test voltage ramp.